A New Era Opens for Understanding the Cellular Basis of Cortical Function

If you want to fix a broken brain, it would be helpful to know how it works. Toward this end, there has been substantial progress in understanding some brain regions. For instance, the field of memory research is now driven by very specific models about the function of the different hippocampal subregions (e.g., dentate, CA3, CA1). Similarly, in the striatum there has been impressive recent research testing very specific ideas about the function of the direct and indirect pathways in action selection. But by comparison, the cortex remains a black box. Although it has been known since the earliest anatomical investigations that the cortex is subdivided into cell layers, little has materialized that provides insight into the function of these layers. The canonical view, based primarily on anatomical considerations, has been that input to cortex occurs in layer 4; this information is sent to layers 2/3, which then send it to layers 5 and 6, the output layers of a cortex. But in terms of showing that this serial pathway actually transforms cortical signals, there is little to point to.

A new paper by Constantinople and Bruno raises the strong possibility that serial processing is not what we should expect. What their study shows is that layer 5 neurons are directly and powerfully activated by thalamic inputsâ€”the inputs which, according to the standard model, are directed primarily to layer 4. Furthermore, the study goes on to verify that thalamic input to layer 4 indeed occurs but is not necessary for the thalamic activation of layer 5. These results thus raise the question, What really is the function of layer 4 and layers 2/3? Here is where new ideas are needed. Perhaps these layers may have more to do with top-down control of covert attention (Graboi and Lisman, 2003) than with direct processing of visual information.

The paper by Constantinople and Bruno is only one of several papers on the cortex that are stunning in their methodological advance. It seems that finally the methods are becoming available that will crack the mystery of the cortex. Notably, it has become possible to study layer 5 cells using biophysical methods and to do so while the animal is awake and performing a task (Xu et al., 2012). Already this work points to a fundamental concept: that layer 5 neurons are not simply adding up their excitatory inputs. Instead, the new work points to the idea that an output burst of spikes requires a very special associationâ€”the feedforward sensory input to parts of the cell near the cell body and feedback input (from higher cortical areas) to the distal dendritic tuft (Larkum, 2013). The coming years are likely to offer a working model of cortical function that will provide the basis for understanding the cortical deficits that occur in schizophrenia.